1. Field of Invention
The present invention relates to an anti-idiotypic antibody and a composition containing same, such as an immunizing composition.
2. Description of the Related Art
Urinary tract infection (UTI) is one of the most common infectious diseases that primarily affect women of all ages. Nearly as many as 50% of all women experience at least one infection in the urinary tract during their lifetimes. Although as prevalent as the common cold, UTI causes far more discomfort and sends 10 million people annually in the United States alone to seek medical attention. Approximately 1.5 million of these visits are diagnosed as pyelonephritis (kidney infection), which is often so serious that hospitalization is required. In addition, approximately 20% of women experience frequent infections (on the order of three to six per year) after the initial episode of UTI, resulting in additional morbidity and lost productivity. It is estimated that five billion healthcare dollars are spent each year to treat UTIs.
Over 85% of all UTIs are caused by the enterobacteria Escherichia coli, and an overwhelming majority of these E. coli bacteria express surface filamentous organelles called Type I fimbriae. Experimental and epidemiological studies have established that Type I fimbriae are the major virulence factor of uropathogenic E. coli, where these fimbriae function as an adhesive apparatus that allows E. coli to bind to the epithelial lining, urothelium, of the urinary tract. Such a binding between the invading E. coli and the host urothelial surface is a pivotal step in the establishment of E. coli colonization within the urinary tract.
Type I fimbriae are hairlike structures which emanate from the surface of E. coli and nearly all members of the Enterobacteriaceae family (Brinton, 1965). The major component of Type I fimbriae is repeating subunits of FimA arranged in a right-handed helix to form a filament approximately 1 xcexcm in length and 7 nm in diameter with a central axial hole (Brinton, 1965). Along with FimA as the major subunit, the fimbrial filament also contains FimF, FimG and FimH as minor protein subunits (Maurer et al, 1987; Abraham et al, 1987; Russel et al, 1992). The minor protein subunit FimH is a mannan-binding adhesin that promotes adherence of Type I-fimbriated bacteria to mannose-containing glycoproteins on eukaryotic cell surfaces and represents a family of proteins which bind to various targets, including mannan and fibronectin (Abraham et al, 1987; Ofek et al, 1977; Sokurenko et al, 1994). Immune electron microscopy studies have revealed that FimH is strategically placed at the distal tips of Type I fimbriae where it appears to be complexed with FimG, forming a flexible fibrillum structure (Abraham et al, 1987 and 1988; Jones et al, 1995), and is also placed longitudinally at various intervals along the filament (Abraham, 1987 and 1988).
While prophylaxis with antibiotics offers quick relief against most UTIs, it is not free from serious drawbacks. For most patients suffering from uncomplicated UTIs, a three-day regimen of trimethoprim/sulfamethozole or a seven-day course of nitrofurandantoin usually stops the infection. However, for some patients, they soon develop side effects, such as vaginitis, gastrointestinal upset and rashes, from the antibiotic, conditions which then require further medical attention. One in five women who experience one infection will experience another infection within weeks. For these patients, a low dose but much longer course (six months to two years) of antibiotics is prescribed to reduce the frequency of reinfections. Although the efficacy of antibiotic prophylaxis for recurrent UTIs has been recently demonstrated, major problems persist in the areas of patient compliance, adverse effects of antibiotics, emergence of bacterial resistance, along with the associated costs of long-term medication. Recent studies show that antibiotic prophylaxis results in a dramatic change in the population of uropathogens reinfecting the host (Reid, 1997). Infections caused by these new strains are generally more difficult to control. Recurrent UTIs not only present a challenge to clinical management, but also significantly increase the risk of kidney involvement, such as pyelonephritis, and complicated UTIs that often require hospitalization and initial parenteral antibiotic therapy. In this situation, a newer generation of antibiotics (e.g., quinolones) or a combination of several antibiotics is usually indicated. However, resistance has been now reported even for these newer generation of antibiotics.
The prevalence of UTIs and the emergence of antibiotic-resistant microorganisms call for novel preventative and therapeutic strategies. One effective approach is the development of vaccines against causative agents of UTIs. The overwhelming majority of UTIs ( greater than 85%) are caused by E. coli, most of which are Type I-fimbriated. Type I fimbriae serve as an adhesive apparatus, via their tip FimH adhesins, for enabling the bacteria to attach to the urothelial surface.
Past efforts in developing a UTI vaccine have been met with limited success. For example, an injectable cocktail containing heat-killed uropathogenic E. coli called Urovac has been available in Europe since the 1980s. However, the efficacy of this vaccine is questionable as it provides limited protection against UTIs. Not only is the protection short-lived, but also the toxins in intact E. coli cause significant side effects, including painful inflammation around the injection sites. To circumvent these problems, a group in Wisconsin tested an alternative delivery method (vaginal suppository) using the same vaccine. Preliminary clinical trials have shown short-term protection against recurrence as UTI-prone patients are less prone to be reinfected. Again, the protection appears to be short-lived. The major drawback of using the entire E. coli as a vaccine also lies in the fact that the FimH adhesin, which is a minor protein in E. coli, is under-presented as an antigen and, thus, unlikely to elicit a sufficient immune response that would target the process of E. coli adherence to the urothelial surface.
A new strategy that was recently tested by a group in St. Louis utilizes recombinant FimH adhesin as a UTI vaccine (Langermann et al, 1997). Immunization of mice with this putative FimH vaccine reduced in vivo colonization of the bladder mucosa by more than 99% in a mouse cystitis model. Immunoglobulin G to FimH was detected in the urine of protected mice. These studies suggest that an anti-FimH approach can be effective in preventing urinary colonization by uropathogenic E. coli (Langermann et al, 1997; Service, 1997). However, there are two major limitations with this approach which, if unresolved, can prevent the FimH-based vaccine from clinical use. First, it is difficult to produce large amounts of FimH protein. FimH expressed alone in E. coli using the recombinant approach is easily degraded. When co-expressed with a chaperone protein (FimD), FimH is somewhat stabilized, but remains at a very low level (Langermann et al, 1997). This can limit the use of FimH as a vaccine. Second, the current putative FimH preparation does not discriminate FimH-carrying uropathogenic E. coli and FimH-carrying intestinal E. coli, the latter of which are beneficial flora. Host immune response targeted against FimH vaccine will likely suppress intestinal E. coli, which could lead to serious side effects (Service, 1997).
Idiotypes have been intensively studied following Jerne""s immune network theory in 1974. One of his major proposals is the self-regulation of the immune system through a network of idiotype-anti-idiotype interactions (Jerne, 1974). It was suggested that the idiotopes on a single antibody molecule can mimic and be the xe2x80x9cinternal imagexe2x80x9d of any foreign or self epitope at the molecular level. Internal image determinants have been proposed for use in vaccines (Nisonoff et al, 1981). By means of Mab technology, a protective antibody (Ab1) to an epitope of interest on the pathogen can be produced. The particular antibody (Ab1) can be purified and subsequently used as an immunogen to elicit an anti-idiotypic antibody (Ab2) which may be an internal image of the original epitope on the pathogen. Thus, as predicted by the Jerne xe2x80x9cnetworkxe2x80x9d theory (Jerne, 1974), immunization with an anti-idiotypic antibody (Ab2) that is directed against antigen combining sites of primary antibody (Ab1), may elicit a humoral immune response specific for the nominal antigen. The resulting anti-anti-idiotypic antibody (or Ab3) should react with the original primary antigen. If the primary antigen is an oligosaccharide (and, therefore, expected to give a T-cell independent immune response), the immunization with Ab2 (the protein equivalent) may elicit a T-cell dependent response.
All idiotypes of a single immunoglobulin molecule have been found to be located on the Fv (fragment variable) region by studies showing that the inhibition of binding of anti-idiotypic antibodies to the idiotype is the same between Fv and Fab. In general, anti-idiotypic antibodies are divided into three types Ab2xcex1, Ab2xcex2 and Ab2xcex5. Only Ab2xcex2, which binds to the complementarity determining region (CDR), can be the internal image of the antigen and has been proposed to be paratropic and to mimic the molecular features of the original antigen (Nisonoff et al, 1981; Roitt, 1985). The occurrence of Ab2 displaying the internal image of the antigen must adhere to the following criteria: (1) binding onto Ab1 and to any other anti-nominal antigen antibodies from another species and lack of reactivity with Ab2 to other antibodies; (2) inhibition of the binding of Ab1 to the specific antigen, the nominal antigen; and (3) the ability to elicit the synthesis of Ab3 with anti-antigen specificity in animals without previous exposure to the antigen.
The important role of anti-idiotypic antibodies in vivo has been shown in numerous experiments. The administration of anti-idiotypic antibodies was found to elicit different effects, either suppression or enhancement of the responses to the specific idiotype (Kennedy, 1983). In autoimmunity, it certainly plays an important role. The pathology associated with many autoimmune diseases is most likely due to (at least in part) a direct idiotype-anti-idiotype interaction of the autoimmune antibodies with anti-idiotypic antibodies. Idiotypic specificity in a specific antibody was first characterized by demonstrating that specific hapten binding could inhibit idiotype recognition.
The best information for the exact molecular basis for the mimicking is presently obtained from the X-ray crystallography of the idiotype-anti-idiotype complex. The basis of molecular mimicry of the antibodies can be either local sequence homology to the original protein as in a reovirus system or, in most cases, identical conformations from entirely different amino acid sequences, as in the hemoglobin-myoglobin family of proteins. X-ray crystallography and sequence data in the later studies showed that identical, functional conformations can be assumed by proteins that differ by as many as 137 of 141 amino acids. The studies of the crystal structure of idiotype-anti-idiotope complex in the anti-lysozyme antibody and the anti-idiotope have demonstrated that a private idiotope consists of 13 amino acid residues, most from the complementarity determining regions (CDRs), but including three residues from the third framework region of its VL domain. Seven of these residues are common with the paratope of anti-lysozyme antibody, indicating a significant overlap between idiotope and antigen-combining site. Idiotype has been a unique tool in the characterization and the manipulation of the immune response since it was discovered as a clonal marker to follow B cell development, somatic mutation and fate of clones of B cells. Idiotypes have been used as a phenotypic marker for germ line V genes.
Anti-idiotypic antibodies, which bear the internal image of external pathogens, such as virus, bacteria or parasites, have been successfully used as surrogate antigens in vaccines (Hiernaux, 1988; Eichmann et al, 1987; Kennedy et al, 1983; Kennedy et al, 1986; McNamara et al, 1984; Schreiber et al, 1990; Schreiber et al, 1990; Stein et al, 1984; Westerink et al, 1988) to elicit a humoral immune response specific for the nominal antigen and are also being used in treating B cell lymphoma and autoimmune disease, such as encephalomyelitis. In addition, it has been shown that anti-idiotypic antibodies can induce T-cell responses in which either toxic T-cells or T-helper cells that recognize the original antigen are produced.
Citation of any document herein is not intended as an admission that such document is pertinent prior art, or considered material to the patentability of any claim of the present application. Any statement as to content or a date of any document is based on the information available to applicant at the time of filing and does not constitute an admission as to the correctness of such a statement.
It is an object of the present invention to solve the problems associated with UTI vaccines. In particular, the present invention overcomes the difficulties associated with a FimH-based UTI vaccine in obtaining large quantities of FimH adhesin and in being specific for uropathogenic Type I-fimbriated E. coli so as to avoid the adverse effects caused by elimination of beneficial intestinal E. coli. 
The present invention provides an anti-idiotypic antibody or an antigen binding fragment thereof which mimics FimH adhesin and serves as a surrogate for FimH in generating a humoral immune response as well as possibly a cellular immune response. Thus, the present invention also provides an immunizing composition and a method for stimulating and enhancing the production of antibodies which recognize and bind to FimH adhesin of uropathogenic Type I-fimbriated Escherichia coli but not to FimH adhesin of non-uropathogenic Type I-fimbriated Escherichia coli by administering the immunizing composition to a subject.